of May 14, 2018.This information is current as

Presentation: Group 1 CD1 ProteinsAn Alternative Path for Antigen

Jack L. Strominger

http://www.jimmunol.org/content/184/7/3303doi: 10.4049/jimmunol.1090008

2010; 184:3303-3305; ;J Immunol 

Referenceshttp://www.jimmunol.org/content/184/7/3303.full#ref-list-1

, 6 of which you can access for free at: cites 27 articlesThis article

        average*  

4 weeks from acceptance to publicationFast Publication! •    

Every submission reviewed by practicing scientistsNo Triage! •    

from submission to initial decisionRapid Reviews! 30 days* •    

Submit online. ?The JIWhy

Subscriptionhttp://jimmunol.org/subscription

is online at: The Journal of ImmunologyInformation about subscribing to

Permissionshttp://www.aai.org/About/Publications/JI/copyright.htmlSubmit copyright permission requests at:

Email Alertshttp://jimmunol.org/alertsReceive free email-alerts when new articles cite this article. Sign up at:

Print ISSN: 0022-1767 Online ISSN: 1550-6606. Immunologists, Inc. All rights reserved.Copyright © 2010 by The American Association of1451 Rockville Pike, Suite 650, Rockville, MD 20852The American Association of Immunologists, Inc.,

is published twice each month byThe Journal of Immunology

by guest on May 14, 2018

http://ww

w.jim

munol.org/

Dow

nloaded from

by guest on May 14, 2018

http://ww

w.jim

munol.org/

Dow

nloaded from

An Alternative Path for Antigen Presentation: Group 1CD1 ProteinsJack L. Strominger

The epochal discovery of a technique for producingmAbs of defined specificity by Georges Kohler andCesar Milstein (1) led to many important advances in

life sciences and spawned a large industry for production ofthese Abs for research, diagnosis, and therapy. The first mouseanti-human mAb produced by this technique was NA1/34. Itrecognized an Ag called HTA-1 (later called CD1a), expressedon human thymocytes and some B lymphoma cell lines (2).Because this and related proteins were among the first humanlymphocyte markers identified with the newly invented mAbtechnology, they entered the immunological lexicon as thefirst cluster of differentiation molecules or “CD1.” Genomicand sequence analysis established that this protein and fourparalogues on human chromosome 1 encoded closely relatedproteins called CD1a, CD1b, CD1c, CD1d, and CD1e,which were distantly related to the H chains of human MHCclass I proteins HLA-A, -B, and -C encoded on chromosome6 (3, 4). Moreover, these proteins were associated with b2-microglobulin, which is encoded on chromosome 15 and alsofound in HLA proteins. On the basis of sequence compar-isons, the molecules could be divided into group 1, com-prising CD1a, CD1b, CD1c, and CD1e, and group 2,containing only CD1d. Surprisingly, however, the mousecontains no group 1 CD1 genes but has two group 2 CD1dgenes, whereas the rat contains only one CD1d, and otherrodents and mammals may contain 8–12 group 1 CD1 genes.Why had these MHC class I-like genes with limited poly-morphism evolved separately from their longer known poly-morphic cousins?

Their function or functions were also obscure, but onceagain, simple but logical direct questions, followed byexperiments, led to the answer. If the function of the poly-morphic MHC class I proteins was to present peptides withdifferent sequences to the immune system, was it possible thatthe CD1 proteins were also Ag-presenting molecules? Werethere circulating T cells that would recognize CD1 molecules?

The answers were provided in three important papers (5–7),the first of which is reprinted here in Pillars of Immunology.Because CD1 proteins are distinct in sequence and structurefrom MHC proteins, T cells that recognize CD1 should not

be MHC restricted. An unusual CD42 CD82 double neg-ative (DN) TCRgd T cell line IDP2 that showed MHC-independent lysis had been described. Among several dozenDN T cell lines that had been generated, equally dividedamong DN TCRab and TCRgd lines, one additional DNTCRab cell line was found that also lysed MOLT4 cells thatdo not express any MHC proteins (5). However, MOLT4was well known to express all three CD1a, CD1b, and CD1cmolecules. mAb blocking experiments established that theTCRs were each involved in the lysis phenomenon. More-over, the unusual DN TCRgd cell line was specific for CD1a,whereas the DN TCRab cell line was specific for CD1c.Later, CD41 (and some CD81) T cells that recognize CD1proteins were found, and the DN characteristic that led to thediscovery diminished in importance.

The door was open. In two subsequent papers, it wasestablished first that a microbial Ag could be presented bya CD1 molecule (6) and then that the foreign Ag was a lipid(7). PBLs were stimulated with an extract of Mycobacteriumtuberculosis, and a cell line, DN1, was obtained that pro-liferated to the extract and to that of M. leprae, but not toseveral other organisms. The Ag extract was presented byCD1-expressing monocytes and was not MHC restricted.Moreover, the response was blocked by CD1b mAb, but notby CD1a or CD1c mAb, nor by pan-MHC class I or MHCclass II mAbs. Further, only CD1b transfectants, not CD1a orCD1c transfectants, could present Ag in the extracts. Thus, inthree short papers, novel T cell lines specific for CD1a,CD1b, or CD1c had been described. The Ag recognized bythe DN1 clone was protease resistant and extractable intoorganic solvents. Reverse phase HPLC was used to show thatthe active component coeluted with mycolic acid, a lipid thatforms the outer coat of mycobacteria. A new class of Ag-presenting proteins had been found for lipid Ags.

The floodgates were open, and a profusion of papers haveappeared in the past 15 y (reviewed in Refs. 8–10). Importantadvances were made in four specific areas: identification of thelipids recognized; crystallization of several CD1 proteins, re-vealing the manner in which lipid moieties lead to binding ofthese Ags; the different trafficking pathways for CD1a, CD1b,and CD1c; and, most importantly, in vivo studies of thepossible role or roles of these CD1 proteins in the patho-genesis of and/or protection from infection. The additionalMHC-like proteins present on human chromosome 1, group2 CD1d and MR1, are beyond the scope of this commentary.

A large number of lipids that bind to the three CD1 proteinshave been identified. Although these molecules have beenreferred to as “lipid Ags,” this label seems a slight misnomerbecause the lipid moieties themselves embed these molecules

Department of Stem Cell and Regenerative Biology and Department of Molecularand Cellular Biology, Harvard University, Cambridge, MA 02138

This work was supported by National Institutes of Health Research Grant AI049524.

Address correspondence and reprint requests to Dr. Jack L. Strominger, Departmentof Molecular and Cell Biology, Harvard University, Fairchild 407, 7 Divinity Avenue,Cambridge, MA 02138. E-mail address: jlstrom@fas.harvard.edu

Abbreviation used in this paper: DN, double negative.

Copyright� 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1090008

by guest on May 14, 2018

http://ww

w.jim

munol.org/

Dow

nloaded from

to the CD1 proteins, whereas hydrophilic head groups of theAgs are recognized by T cells. The lipids are mainly glyco-lipids and lipopeptides, and only in rare cases, like mycolicacid, is the lipid itself recognized. “Lipid-linked Ags” wouldbe a more precise term. Many of the lipids recognized comefrom important human pathogens such as M. tuberculosis, M.leprae, Leishmania, and Borrelia burgdorferi (the causativeagent of Lyme disease). In mycobacteria, for example, up to40% of the cell wall may be composed of lipids.

CD1a and CD1b were crystallized. The resulting structuresdemonstrated different ways that lipids are bound to theseproteins. Both use hydrophobic pockets called A9 and F9 tobind lipids (related in position and function to the A and Fpockets in MHC class I proteins that bind amino acid sidechains). CD1b also has a C9 pocket that mainly providesa portal to the exterior and a T9 (for tunnel) pocket, featuresthat may allow accommodation of very large lipids (11–13). Acomputational model of the CD1c structure has recentlyappeared. It is distinguished from its close cousins by the sizeof the F9 pocket; the absence of pockets C9 and T9; and thepossible presence of a new portal, D9 (14).

The distinctive trafficking pathways of the group 1 CD1proteins that lead to loading of the lipid-linked Ags are mostinteresting (10). After biosynthesis in the endoplasmic re-ticulum and Golgi, where binding of self-lipids occurs, thesemolecules first travel to the cell surface. Direct loading oflipids may occur at the surface, but in addition these proteins,although they resemble MHC class I proteins structurally,traffic through the endosomal compartments, where loadingand/or exchange with exogenous lipid-linked Ags occurs, ina manner similar to the MHC class II proteins. The threegroup 1 CD1 proteins have distinct trafficking pathways.CD1a, which has only a short cytoplasmic tail, remains largelyat the surface and follows the shallow endosomal recyclingpathway of MHC class I. By contrast, CD1b and CD1c havelonger tails encoding endosomal sorting motifs that use AP2and AP3 as trafficking carriers to late endosomal compart-ments. CD1c appears to traffic broadly to both early and lateendosomes (lysosomes), whereas CD1b mainly traffics both tothe same endosomes in which peptide loading on MHC classII proteins occurs and more deeply to late endosomes. In thesepathways, they encounter lipid-linked Ags derived frompathogens in phagolysosomes. Lipid loading presumably re-quires some form of assistance. Saposins and apolipoproteins(15, 16) have been suggested to play an important role in thisprocess, but in addition the fourth group 1 CD1 molecule,CD1e, may also have a significant part in lipid loading (17,18). Interestingly, loading of peptides onto MHC class IImolecules requires the assistance of the class II-like proteinHLA-DM. Even the classical MHC class I molecules haveamong them HLA-F that resides in the endoplasmic re-ticulum and has no known function. Could it also, in somecircumstances, be involved in loading of peptides onto MHCI proteins?

After loading lipid-linked Ags, CD1b and CD1c moleculesreturn to the cell surface, where they can be recognized by Tcells. Thus a new system for recognizing lipid-linked Ags wasdescribed in addition to the longer known peptide recognitionsystem involving MHC class I and MHC class II proteins.

However, important work often ends in important ques-tions. What is the role of CD1 proteins in the pathogenesis of

and/or protection from infection? Can the information gainedbe used to develop vaccines against important pathogens,particularly M. tuberculosis, which causes worldwide mor-bidity and mortality nearly equal to that of HIV and has beena plague at least since the time of the pharaohs? Expansion ofCD1-restricted T cells and secretion of IFN-g has been clearlydemonstrated in infections, particularly those with M. tuber-culosis (19, 20). At this point, though, data indicating thatthese T cell responses are protective are still lacking. Micro-organisms also have been reported to be able to either upre-gulate or downregulate expression of CD1 proteins onmonocytes (10, 21, 22) (K. Yakimchuk, C. Roura-Mir, T.-Y.Cheng, S. R. Granter, R. Budd, A. Steere, V. Pena-Cruz, andD. B. Moody, submitted for publication). Because the mouselacks group 1 CD1 proteins, a mouse model has not beenavailable. However, the recent construction of a mousetransgenic for human CD1a, CD1b, and CD1c may make itpossible to design an experiment in which protection can bedemonstrated (23). Similarly few data on vaccination withlipid-linked Ags are available (24–27). Of particular interest isa recent study of cattle immunized with mycobacterial glucosemonomycolate (27). Cattle express CD1a, CD1b, and CD1c,but no CD1d. In this species, infections with M. bovis andM. avium subsp. paratuberculosis cause important economicproblems. Strong T cell responses to immunization weregenerated. Much work in this area remains to be done, but thebasic scientific foundations have been laid.

DisclosuresThe author has no financial conflicts of interest.

References1. Kohler, G., and C. Milstein. 1975. Continuous cultures of fused cells secreting

antibody of predefined specificity. Nature 256: 495–497.2. McMichael, A. J., J. R. Pilch, G. Galfre, D. Y. Mason, J. W. Fabre, and C. Milstein.

1979. A human thymocyte antigen defined by a hybrid myeloma monoclonal an-tibody. Eur. J. Immunol. 9: 205–210.

3. Calabi, F., and C. Milstein. 1986. A novel family of human major histocompati-bility complex-related genes not mapping to chromosome 6. Nature 323: 540–543.

4. Calabi, F., and C. Milstein. 2000. The molecular biology of CD1. Semin. Immunol.12: 503–509.

5. Porcelli, S., M. B. Brenner, J. L. Greenstein, S. P. Balk, C. Terhorst, andP. A. Bleicher. 1989. Recognition of cluster of differentiation 1 antigens by humanCD42CD82cytolytic T lymphocytes. Nature 341: 447–450.

6. Porcelli, S., C. T. Morita, and M. B. Brenner. 1992. CD1b restricts the response ofhuman CD4282 T lymphocytes to a microbial antigen. Nature 360: 593–597.

7. Beckman, E. M., S. A. Porcelli, C. T. Morita, S. M. Behar, S. T. Furlong, andM. B. Brenner. 1994. Recognition of a lipid antigen by CD1-restricted alpha beta1

T cells. Nature 372: 691–694.8. Moody, D. B. 2006. The surprising diversity of lipid antigens for CD1-restricted T

cells. Adv. Immunol. 89: 87–139.9. Bricard, G., and S. A. Porcelli. 2007. Antigen presentation by CD1 molecules and

the generation of lipid-specific T cell immunity. Cell. Mol. Life Sci. 64: 1824–1840.10. Cohen, N. R., S. Garg, and M. B. Brenner. 2009. Antigen presentation by CD1

lipids, T cells, and NKT cells in microbial immunity. Adv. Immunol. 102: 1–94.11. Gadola, S.D.,N. R.Zaccai, K.Harlos,D. Shepherd, J. C.Castro-Palomino,G.Ritter,

R. R. Schmidt, E. Y. Jones, and V. Cerundolo. 2002. Structure of human CD1b withbound ligands at 2.3 A, a maze for alkyl chains. Nat. Immunol. 3: 721–726.

12. Moody, D. B., D. M. Zajonc, and I. A. Wilson. 2005. Anatomy of CD1-lipidantigen complexes. Nat. Rev. Immunol. 5: 387–399.

13. Zajonc, D. M., and I. A. Wilson. 2007. Architecture of CD1 proteins. Curr. Top.Microbiol. Immunol. 314: 27–50.

14. Garzon, D., P. J. Bond, and J. D. Faraldo-Gomez. 2009. Predicted structural basisfor CD1c presentation of mycobacterial branched polyketides and long lipopeptideantigens. Mol. Immunol. 47: 253–260.

15. Zhou, D., C. Cantu III, Y. Sagiv, N. Schrantz, A. B. Kulkarni, X. Qi, D. J. Mahuran,C. R. Morales, G. A. Grabowski, K. Benlagha, et al. 2004. Editing of CD1d-boundlipid antigens by endosomal lipid transfer proteins. Science 303: 523–527.

16. van den Elzen, P., S. Garg, L. Leon, M. Brigl, E. A. Leadbetter, J. E. Gumperz,C. C. Dascher, T. Y. Cheng, F. M. Sacks, P. A. Illarionov, et al. 2005. Apolipo-protein-mediated pathways of lipid antigen presentation. Nature 437: 906–910.

3304 PILLARS OF IMMUNOLOGY

by guest on May 14, 2018

http://ww

w.jim

munol.org/

Dow

nloaded from

17. de la Salle, H., S. Mariotti, C. Angenieux, M. Gilleron, L. F. Garcia-Alles,D. Malm, T. Berg, S. Paoletti, B. Maıtre, L. Mourey, et al. 2005. Assistance ofmicrobial glycolipid antigen processing by CD1e. Science 310: 1321–1324.

18. Tourne, S., B. Maitre, A. Collmann, E. Layre, S. Mariotti, F. Signorino-Gelo,C. Loch, J. Salamero, M. Gilleron, C. Angenieux, et al. 2008. Cutting edge:a naturally occurring mutation in CD1e impairs lipid antigen presentation. J. Im-munol. 180: 3642–3646.

19. Gilleron, M., S. Stenger, Z. Mazorra, F. Wittke, S. Mariotti, G. Bohmer, J. Prandi,L. Mori, G. Puzo, and G. De Libero. 2004. Diacylated sulfoglycolipids are novelmycobacterial antigens stimulating CD1-restricted T cells during infection withMycobacterium tuberculosis J. Exp. Med. 199: 649–659.

20. Moody, D.B., T. Ulrichs, W. Muhlecker, D. C. Young, S. S. Gurcha, E. Grant,J. P. Rosat, M. B. Brenner, C. E. Costello, G. S. Besra, and S. A. Porcelli. 2000.CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacteriumtuberculosis infection. Nature 404: 884–888.

21. Baena, A., and S. A. Porcelli. 2009. Evasion and subversion of antigen presentationby Mycobacterium tuberculosis. Tissue Antigens 74: 189–204.

22. Kasmar, A., I. Van Rhijn, and D. B. Moody. 2009. The evolved functions of CD1during infection. Curr. Opin. Immunol. 21: 397–403.

23. Felio, K., H. Nguyen, C. C. Dascher, H. J. Choi, S. Li, M. I. Zimmer, A. Colmone,D. B. Moody, M. B. Brenner, and C. R. Wang. 2009. CD1-restricted adaptiveimmune responses to Mycobacteria in human group 1 CD1 transgenic mice. J. Exp.Med. 206: 2497–2509.

24. Hiromatsu, K., C. C. Dascher, K. P. LeClair, M. Sugita, S. T. Furlong,M. B. Brenner, and S. A. Porcelli. 2002. Induction of CD1-restricted immuneresponses in guinea pigs by immunization with mycobacterial lipid antigens.J. Immunol. 169: 330–339.

25. Dascher,C.C.,K.Hiromatsu,X.Xiong,C.Morehouse,G.Watts,G.Liu,D.N.McMurray,K. P. LeClair, S. A. Porcelli, andM. B. Brenner. 2003. Immunization with a mycobacteriallipid vaccine improves pulmonary pathology in the guinea pig model of tuberculosis. Int.Immunol. 15: 915–925.

26. Singh, A. P., and G. K. Khuller. 1994. Induction of immunity against exp-erimental tuberculosis with mycobacterial mannophosphoinositides encapsulated inliposomes containing lipid A. FEMS Immunol. Med. Microbiol. 8: 119–126.

27. Nguyen, T. K., A. P. Koets, W. J. Santema, W. van Eden, V. P. Rutten, and I. VanRhijn. 2009. The mycobacterial glycolipid glucose monomycolate induces a mem-ory T cell response comparable to a model protein antigen and no B cell responseupon experimental vaccination of cattle. Vaccine 27: 4818–4825.

The Journal of Immunology 3305

by guest on May 14, 2018

http://ww

w.jim

munol.org/

Dow

nloaded from